My post-doctoral work suggests two possible explanations for why cancer cells might need to co-activate multiple RTKs. First, I found that activated RTKs additively contribute to cell growth and downstream signaling, such that the genetic or pharmacological inhibition of any individual RTK only partially blocks these functions. Second, I found that RTKs can replace one another in signaling complexes to maintain oncogenic signaling when a particular RTK is lost. Both these observations suggest that the individual identities of activated RTKs might not be as important for tumor growth as meeting a threshold of signaling with a minimum number of RTKs. In contrast, another explanation for why cancer cells might need multiple co-activated RTKs is that each RTK makes a separate contribution to tumor physiology: for example, perhaps one RTK promotes angiogenesis, another cell survival, and a third cell movement. To distinguish between these possibilities, we are addressing the impact of combinatorial RTK signaling on cellular transformation, malignant phenotypes, and downstream signaling using the following approaches: 1) examining the effects of RTK co-expression on the growth of immortalized normal human astrocytes and tumor neurospheres in culture and in a mouse orthotopic brain tumor system and 2) performing genetic screens to identify classes of cooperating RTKs.